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dc.contributor.advisorGustafsson, Jan-Åke
dc.creatorMuthusamy, Selvaraj 1980-
dc.date.accessioned2015-02-20T15:25:26Z
dc.date.available2015-02-20T15:25:26Z
dc.date.createdMay 2014
dc.date.issued2014-05
dc.identifier.urihttp://hdl.handle.net/10657/918
dc.description.abstractEstrogen receptor β is a nuclear receptor expressed in various tissues in the body including prostate and brain. In addition to 17β-estradiol, other steroids like 5α-androstane-3β, 17β-diol (3β-Adiol) and 5-androstene-3β, 17β-diol have been reported to be endogenous ligands of ERβ. The concentration of these ligands in the tissue and the metabolism of these ligands by different enzymes regulate the transcriptional activity of ERβ. In human prostate, 3β-Adiol acts on ERβ to exert an anti-proliferative effect to counteract the proliferative activity of 5α-dihydrotestosterone (DHT) mediated through androgen receptor. 3β-Adiol is produced from 5α-dihydrotestosterone. In chapter 2, we show that 17β-HSD6, a predominant enzyme expressed in human prostate, converts DHT to 3β-Adiol. This conversion of DHT to 3β-Adiol is capable of activating ERβ at physiological concentrations of DHT. Immunohistochemical analysis revealed that 17β-HSD6 is expressed in ERβ-positive epithelial cells of the human prostate and that, both ERβ and 17β-HSD6 were present in benign prostatic hyperplasia (BPH) samples and were undetectable in prostate cancers of Gleason grade higher than 3. These observations reveal that formation of 3β-Adiol via 17β-HSD6 from DHT is an important growth regulatory pathway that is lost in prostate cancer. ERβ plays an important role in development and homeostasis of brain. In chapter 3, using liquid extraction, solid phase extraction and LC-MS/MS, we show that estrone is the only detectable endogenous ligand of ERβ in mouse brain tissue. We also show that CYP7B1 knockout mice have significantly higher level of estrone compared to the sex matched wild type controls. We show that only 25% of estrone is converted to estradiol by brain tissue after 24 h of incubation, which indicates that the conversion of estrone to estradiol by brain tissue is very slow. Using cell based transactivation assays we show that estrone is capable of activating ERβ with an EC50 of 3.5 nM. Since the concentration of estrone in mouse brain is 25 nM to 35 nM, estrone could be a physiological ligand of ERβ in mouse brain.
dc.format.mimetypeapplication/pdf
dc.language.isoeng
dc.subjectERβ
dc.subjectsteroids
dc.subjectligands
dc.subjectnuclear receptor
dc.subjectmass spectrometry
dc.subjectLC-MS
dc.subjectenzyme
dc.subject17β-HSD6
dc.subjectprostate
dc.subjectcancer
dc.subjectbrain
dc.subject3β-Adiol
dc.subjectAndrostanediol
dc.subjectDHT
dc.subjectDihydrotestosterone
dc.subjectEstradiol
dc.subjectEstrone.
dc.subject.lcshCytology
dc.titleLigands of Estrogen Receptor β in Prostate and Brain
dc.date.updated2015-02-20T15:25:26Z
dc.type.genreThesis
thesis.degree.nameDoctor of Philosophy
thesis.degree.levelDoctoral
thesis.degree.disciplineBiology
thesis.degree.grantorUniversity of Houston
thesis.degree.departmentBiology and Biochemistry
dc.contributor.committeeMemberMoore, David
dc.contributor.committeeMemberWarner, Margaret
dc.contributor.committeeMemberZhang, Weihua
dc.type.dcmiText
dc.format.digitalOriginborn digital
thesis.degree.majorCell and Molecular Biology
dc.description.departmentBiology and Biochemistry
thesis.degree.collegeCollege of Natural Sciences and Mathematics


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